Asymmetric Hydrogenation of Allylic Alcohols Using IrâN,P

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Asymmetric hydrogenation of allylic alcohols using Ir-N,P-complexes. Jia-Qi Li, Jianguo Liu, Suppachai Krajangsri, Napasawan Chumnanvej, Thishana Singh, and Pher G. Andersson ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02456 • Publication Date (Web): 31 Oct 2016 Downloaded from http://pubs.acs.org on October 31, 2016

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Asymmetric hydrogenation of allylic alcohols using Ir-N,Pcomplexes. Jia-Qi Li,[a] Jianguo Liu,[b] Suppachai Krajangsri,[b] Napasawan Chumnanvej,[b] Thishana Singh[b] and Pher G. Andersson*[b] [a] Department of Applied Chemistry, China Agricultural University, Beijing, 100193, China ([email protected]) [b] Department of Organic Chemistry, Stockholm University, 106 91, Stockholm, Sweden. ([email protected]) KEYWORDS asymmetric synthesis • γ,γ-disubstituted allylic alcohols • β,γ-disubstituted allylic alcohols • DFT • iridium • hydrogenation

ABSTRACT: In this study, a series of γ,γ-disubstituted and β,γ-disubstituted allylic alcohols were prepared and successfully hydrogenated using suitable N,P-based Ir-complexes. High yields and excellent enantioselectivities were obtained for most of the substrates studied. This investigation also revealed the effect of the acidity of the N,P-Ir-complexes on the acid sensitive allylic alcohols. DFT ∆pKa calculations was used to explain the effect of the N,P-ligand on the acidity of the corresponding Ir-complex. The selectivity model of the reaction was used to accurately predict the absolute configuration of the hydrogenated alcohols.

Introduction Enantioenriched alcohols provide a valuable feedstock for the synthesis of bioactive natural products1 and pharmaceuticals2 since the hydroxyl group can be readily transformed to other functional groups, most often in a high stereospecific manner.3 Furthermore derivatives of alcohols bearing stereogenic centers on the β- and or γ-carbon also exist widely in natural products,4 pharmaceuticals,5 agrochemicals6 and fragrances.7 Transition-metal catalyzed asymmetric hydrogenation has emerged as one of the most powerful tools for the preparation of chiral compounds in both academic research and industrial production. Some attractive features of this transformation include high enantioselectivity, low catalyst loadings, high yields, mild reaction conditions and nearperfect atom economy.8 The enantioselective reduction of allylic alcohols constitutes a useful and practical route affording the corresponding optically active alcohols in a single step.9 Originally, Rh- and Rudiphosphine complexes were utilized and high enantioselectivities have been obtained. Rh-complexes generally result in high ees for the asymmetric hydrogenation of allylic alcohols bearing at least one aryl group on the γ-carbon.10 When Rh complexes are employed as catalysts, high catalyst loading and often long reaction times are required.11 Despite the high enantioselectivities achieved using Ru catalysts, the scope of the reaction, especially considering substrates bearing aliphatic substituents is quite limited.12 Highly diastereoselective hydrogenations of allylic alcohols have also been achieved using N-heterocyclic carbenes (NHCs), N-based Ircomplexes.13 For asymmetric hydrogenation using Ircomplexes, only a few catalysts have been shown to give high enantioselctivities14 and the reduction often resulted in complex mixtures.15 Notably, the isomerization of C=C is often

observed as a competitive process when using Rh, Ru and Ircomplexes in the hydrogenation, especially at low pressure.16 Overall, allylic alcohols remain challenging substrates in transition-metal catalysed asymmetric hydrogenation. The N,P-ligated Ir-complexes have recently proved to be effective catalysts for the asymmetric hydrogenation of alkenes having little or no functionality.8a,17 It has been shown that alkenes bearing Lewis basic substituents can coordinate to Ir and this effect may influence the performance of catalysts in the hydrogenation process.18 It is well-known that Crabtree's iridium catalyst often shows a high tendency to coordinate to alcohol groups in the substrate resulting in highly diastereoselective hydrogenations. This was studied by Stork and coworkers where it was discovered that there was coordination to Ir in the hydrogenation of both homoallylic and allylic alcohols using Crabtree’s catalyst [(PCy)3(Pyridine)Ir(COD)]+[PF6]-.19 However there exists no clear evidence for this coordination in asymmetric iridiumcatalysed hydrogenations, where the monodentate phosphine and pyridine ligands have been replaced by a bulky, bidentate chiral N,P-ligand. In a computational study carried out by Burgess and co-workers, it was found that a 2-substituted allylic alcohol (2-methylbut-2-en-1-ol) did not coordinate to Ir during the hydrogenation.20 Also, recent studies by Pfaltz did not provide any evidence for strong coordination between the hydroxyl group and Ir.14d,21 Successful examples of asymmetric hydrogenations of allylic alcohols with Ir-complexes do exist.14,17b,22 There are numerous derivatives of (E)-cinnamyl alcohols that have been hydrogenated with high enantioselectivity, but the (Z)cinnamyl alcohols usually gave lower reactivities and selectivities.14d Dialkylsubstituted allylic alcohols were also difficult to hydrogenate in high enantioselectivities.23 In fact, it has been shown in the Ir-catalyzed asymmetric hydrogenation, that

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high enantioselectivities are easy to obtain for alkenes bearing at least one aryl substituent on the prochiral carbon. This is partially attributed to π-π interaction between the aryl ring and the catalyst.24 Pure alkyl substituted alkenes usually result in low ees in this transformation. This is possibly due to the similar size of the substituents and the lack of interaction between the substrate and catalyst resulting in the difficulty to distinguish the Re and Si faces in the hydrogenation process.10b Overall, the substrate scope in the Ir-catalyzed asymmetric hydrogenation of allylic alcohols is still limited. Moreover, dialkyl and (Z)-allylic alcohols remain difficult substrates in transition-metal catalyzed asymmetric hydrogenation. Thus, there is still room to explore new complexes for the efficient hydrogenation of diverse allylic alcohols. We have previously shown the highly enantioselective hydrogenation of functionalized olefins using Ir-N,P catalysts.25 As an extension of our study, we now report the asymmetric hydrogenation of a wide range of disubstituted allylic alcohols with the intention to study the substrate scope in the Ircatalyzed asymmetric hydrogenation.

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enantioselectivities and yields. Substrates 4-6 gave excellent ees and over 95% isolated yields. Chiral diarylmethine compounds are present in numerous natural products and bioactive compounds.28 The diaryl- substituted allylic alcohol 729 was employed in the hydrogenation and produced excellent results: 96% yield and 95% ee. Table 1. Asymmetric hydrogenation of γ-substituted cinnamyl alcohols[a]

Figure 1. Catalysts used in this study.26

Results and Discussion The asymmetric hydrogenation of γ-substituted cinnamyl alcohol was chosen for the initial study (Table 1). In the hydrogenation of (E)-allylic alcohol 1, catalyst A (Figure 1) gave an excellent ee of 98% and a high isolated product yield was also obtained. No isomerization product, 3-phenylbutanal, was detected by 1H NMR under the reaction conditions used. The impact of steric and electronic effects on the enantioselectivity is often a problem in the Ir-catalyzed asymmetric reaction27 and we were pleased to see that significant structure variation in the substituents on C=C was tolerated without affecting the ee in this hydrogenation. Electron donating or withdrawing groups at the para position of the aryl ring only affected the hydrogenation slightly (substrates 2 and 3). The resulting chiral saturated alcohols were obtained with excellent yields and enantioselectivities. Sterically bulkier substituents (ethyl, isopropyl and cyclohexyl) had no significant influence on

[a] Reaction conditions: 0.25 mmol of substrate, 1.0 mol % catalyst, 2 mL of CH2Cl2, 50 bar H2. 17h, r.t. [b] Isolated product yields. [c] Determined by chiral GC or HPLC analysis, see Supporting Information for details. [d] Assignment of absolute configuration is based on literature reference. [e] Absolute configuration of the hydrogenated product was tentatively assigned based


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on elution order. [f] Reaction carried out under 100 bar H2. [g] Conversion determined by 1H NMR.

When compared to a similar study of the hydrogenation of diaryl-substituted allylic alcohols using an imidazole catalyst, this hydrogenation does not need a special solvent, α,α,αtrifluorotoluene, and was carried out at 50 bar H2 instead of 100 bar H2.14a Recently, Ding and co-workers reported a Rhcatalysed asymmetric hydrogenation of β,β-diarylpropionic acids prepared from the hydroxylation of 3,3-diarylacrylates. Similar enantioselectivities (up to 96% ee) were achieved, however, in that case a mixed-ligand approach had to be used in order to obtain enough activity and morpholine had to be used as base.30 The influence of the stereochemistry of the C=C on both reactivity and enantioselectivities are frequently observed in hydrogenation reactions. In contrast to (E)-configured alkenes, the corresponding (Z)-alkenes are usually more difficult to hydrogenate and generally result in lower enantioselectivities in the Ir-catalysed asymmetric hydrogenation.21 However, substituted (Z)-configured cinnamyl alcohols were also successfully hydrogenated. Higher catalyst loading, H2 pressure or longer reaction time were not required to achieve full conversion when using the same substrate concentration and temperature as (E)-olefins. Instead, enantioselectivities were found to be sensitive to the steric bulk of the substituent close to the C=C. In the hydrogenation of (Z)-allylic alcohols 8 and 9, complex C was found to be the most selective catalyst. The methyl substituted substrate 8 gave an excellent ee of 95%, whereas only 86% ee was obtained for the ethyl derivative 9. An excellent ee of 93% was obtained in the hydrogenation of n-Bu substituted allylic alcohol 10. Complex D was the most selective catalyst for the hydrogenation of sterically more demanding substrates (substrates 11 and 12). Perfect selectivity (98% ee) was obtained for the hydrogenation of cyclohexyl substituted substrate 12. The reduction of (Z)-configured substrates 8-12 was very clean with excellent isolated product yields of between 92-98% being attained. No double bond isomerization products, aldehydes or (E)-configured allylic alcohols were detected under the reaction conditions used. Diol 13 was also successfully hydrogenated. As the synthetic equivalent of 2-substituted succinic acid derivatives, the hydrogenation product can function as valuable and important building blocks in the syntheses of biologically active compounds and natural products.38 With a few exceptions, high enantioselectivities have previously only been reported for alkenes bearing aryl groups on C=C. Pure alkyl substituted alkenes are still considered challenging substrates in the asymmetric hydrogenation using IrN,P-complexes.8a,17 High enantioselectivities and diastereoselectivities have been achieved in the hydrogenation of allylic alcohols bearing two or more C=C bonds8a e.g. farnesol and with a stereogenic center adjacent to the C=C bond.13 However, the diversity of substrates was quite limited. In a previous study on the hydrogenation of γ,γ-dialkylsubstituted allylic alcohols, (E)- and (Z)-3-methyl-5-phenylpent-2-en-1-ol, gave only moderate enantioselectivities (64% ee for (E)configured isomer and 69% ee for the (Z)-isomer) using IrPHOX complex.23 In the asymmetric hydrogenation of (E)- 3methyl-5-phenylpent-2-en-1-ol 14, catalyst B proved to be the best catalyst in the catalyst screening. Substrates 14-16, bearing 3-phenylpropyl, benzyl and neopentyl on C=C, gave good to excellent enantioselectivities (78-91% ees). A more sterical-

ly demanding cyclohexyl group as the substituent (substrate 17) resulted in a much lower enantioselectivity. In the asymmetric hydrogenation of (Z)-crotyl alcohols, complex C was found to be the most selective catalyst. Only the neopentyl substituted allylic alcohol 21 gave a poor ee. Interestingly, when the steric hindrance of the substituent became smaller (ethyl, 2-phenylethyl and benzyl) or larger (cyclohexyl), excellent enantioselectivities (over 90% ees) were obtained (substrates 18, 19, 20 and 22). Table 2. Asymmetric hydrogenation of dialkyl substituted allylic alcohols[a]

[a]-[e] See the corresponding footnotes in Table 1. [f] Absolute


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configuration of the hydrogenated product was tentatively assigned based on specific optical rotation. [g] Absolute configuration of the hydrogenated product was tentatively assigned based on elution order and specific optical rotation. [h] Reaction carried out with 1.5 mol % catalyst under 100 bar H2. [i] Reaction carried out under 100 bar H2. [j] Conversion determined by 1H NMR.

Nevertheless, the asymmetric hydrogenation of all dialkylsubstituted substrates gave the corresponding saturated alcohols in excellent isolated yields. For substrates 23, 24 and 25, the substituent was varied from ethyl to isopropyl and cyclohexyl. Both the yield and ee for 24 decreased however for the larger cyclohexyl 25, it increased. The cyclic allylic alcohol 26 gave high ee whereas the more strained 5-membered substrate 27 was hydrogenated with a lower yield and ee which is also consistent with previous findings.48 Hydrogenation of two β,γdialkyl substituted allylic alcohols was also attempted. Complex J was the most selective catalyst for substrate 28 and catalyst C gave the best results for allylic alcohol 29. The resulting saturated alcohols of these two aliphatic allylic substrates has numerous applications.49 Hydrogenation of geraniol and nerol was also attempted under the standard hydrogenation conditions. (See Supporting Information for details.) However, both the C2/C3 and C6/C7 double bonds were hydrogenated. Similar observations have been reported with Ir(I) complexes.50 The mechanism of Ir-catalyzed asymmetric hydrogenation of unfunctionalized olefins proceeding first through migratoryinsertion and then a reductive-elimination sequence involving [IrIII(H)2(alkene)(H2)(N,P)]+ and [IrV(H)3(alkyl)(N,P)]+ as the key reactive intermediates was originally supported by Density Functional Theory (DFT) calculations51 and has recently been investigated by an experimental study.52 In this catalytic cycle, olefin coordination occurs cis to the chelating N, and is followed by the migratory-insertion step. A simple quadrant model can be derived from this coordination and rationalizes the observed enantioselectivities based on this IrIII/IrV pathway in which the migratory-insertion is considered as the rate- and enantio-determining step for the hydrogenation of trisubstituted olefins.53 The space surrounding Ir in an Ir-N,P-complex is divided into four quadrants (Figure 2a). It is clear that the space occupied by the ortho- substituent of sp2-hybridized nitrogen on the heterocyclic ring is the most hindered quadrant. Thus, the trisubstituted olefin orients its smallest substituent, a vinylic proton, toward the most hindered quadrant when it coordinates to Ir.

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Table 3. Correlation of observed and predicted absolute configurations.

Hence, the absolute configuration of the major product formed in the asymmetric hydrogenation of a trisubstituted olefin using this type of catalyst can be predicted by determining if the ligand places the substituent of the N-heterocycle above or below the N–Ir–P plane (Figure 2b). The absolute configurations of the majority of the allylic alcohol products are known and reported in the literature (Table 1 and 2). This data was used to evaluate the selectivity model with a variety of substrates. By comparing the specific optical rotation and/or GC-MS/HPLC elution order, it was found that the stereochemistries of all the saturated alcohols investigated in the asymmetric hydrogenation are consistent with the predicted configurations from the selectivity model (Table 3).


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Figure 2. Quadrant model for predicting the absolute configuration in the asymmetric hydrogenation of trisubstituted alkenes using Ir-N,P-complexes. a) steric environment around Ir. b) 3-D model for asymmetric hydrogenation of allylic alcohols 10 and 12.

Transition-metal-hydride complexes can be considered as potential Lewis acids or Brønsted acids.54 There are a number of transformations catalyzed by metal-hydrides based on their acidity.55 Moreover, reactivities of these complexes and the results of reactions they catalyze, are directly related to their acidities which are presented as pKa values.56 The N,P and NHCs, N-based Ir-complexes are the two major types of catalysts that are chiral mimics of Crabtree’s catalyst and are used in the asymmetric hydrogenation of olefins with or without coordinating functional groups. In our previous study27a of the asymmetric hydrogenation of some acid sensitive enol ethers using N,P based Ir-complexes, base had to be added in the hydrogenation to avoid side reactions that may be caused by proton generation by the Ir catalyst. Base was also required using NHCs-based Ir-complexes.57 Recently, Burgess and coworkers showed that NHCs-based Ir-complexes are less acidic than N,P based Ir-complexes. This difference in acidity can be explained by the electronic features of the NHCs and the phosphine ligands. The NHCs is a superior σ-donor and an inferior π-acceptor, this results in a more electron rich complex from which protons are more difficult to dissociate from Ir.58 In this work, a number of different N-heterocyclic ligand donors have been studied which includes imidazoles (complex F, G), thiazoles (complex A, D, E) and oxazoles (complex I). A combination of DFT energy calculations and experimental studies indicates that the basicity of the N-heterocycles has a significant contribution on the relative acidity of the corresponding N,P-based Ir-complexes.

The pKaH of the parent 5-membered protonated heterocycles is as follows: imidazole has a pKaH of 7.0 and is classified as a medium strong base; thiazole is less basic with a pKaH of 2.5 and oxazole has a pKaH of 0.8 (Figure 3a). The experimental pKaH were measured in dimethylsulfoxide.59 The ∆G values for the metal hydrides in the deprotonation reactions as depicted in the acid-base relationship (Figure 3a) was calculated and used to generate the ∆pKa values. Since one pKa unit corresponds to 1.37 kcal.mol-1 difference in free energy,60 ∆pKa values were calculated for the Ir-complexes (Figure 3b) in dimethylsulfoxide and dichloromethane. A similar trend for the ∆pKa values was observed in both solvents. (Calculation details and XYZ coordinates with energies are available in the Supporting Information.) The oxazole complex I was calculated to have the lowest energy. The energy differences were then measured relative to complex I which was set to zero. Allylic alcohols can be considered as relatively acid sensitive compounds. Protonation of the hydroxyl group and subsequent elimination of water, results in the generation of an allyl carbocation. It was assumed that the reason for the complex mixture of reaction products that was observed in some of the hydrogenations was due to the formation of carbocation intermediates. Several allylic alcohols that can generate different types of carbocations were tested in the hydrogenation using a set of catalysts based on different heterocycles.


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Figure 3. a) Acid-base relationship of metal hydrides. b) pKaH of the protonated heterocycles and trend depicting the decrease of ∆pKa values in dichloromethane as the N donors varied.

tertiary allylic alcohol 33 was used as substrate, an intramolecular Friedel–Crafts reaction took place instead of hydrogenation (Scheme 1).

Figure 4. Performance of Ir-complexes in hydrogenation of acid sensitive compounds.

In the hydrogenation of primary allylic alcohol 30, excellent yields (over 99%) were obtained with all catalysts. This is possibly due to the difficulty in the formation of the primary carbocation. When the secondary allylic alcohol 31, bearing a methyl group on the allylic position, was applied in the hydrogenation the amount of desired hydrogenation products follow the order F > G > E > H > I which is consistent with the decreasing basicity of the heterocycle in the ligand (Figure 4). The same trend was observed for the hydrogenation of the phenyl substituted secondary allylic alcohol 32 and resulted in a lower yield of hydrogenated product since the generation of the carbocation is easier when the phenyl group is in the allylic position. Furthermore, when the diphenyl substituted

Scheme 1. Intramolecular Friedel–Crafts alkylation catalyzed by Ir-complexes under H2 Racemic 36 (determined by chiral HPLC analysis) was obtained as the sole product and the C=C hydrogenation product 38 could not be detected by 1H NMR. The Friedel-Crafts product 36 is a tetrasubstituted olefin which is usually difficult to hydrogenate using Ir-N,P catalysts.61 The cyclization of allylic alcohol 33 has earlier been reported to take place using strongly acidic conditions (Brønsted acid, e.g. FSO3H-SO262 and Lewis acid, e.g FeCl3·6H2O63) as depicted in Scheme 1. The hydrogenation of the acid sensitive enol acetate was also attempted. When 39 with an alkyl substituent was used as substrate, only the imidazole complex F gave full conversion and excellent yield. No conversions were observed using catalyst G, E, H and I. The hydrogenation of the phenyl sub-


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stituent enol acetate 40 resulted in complex mixtures with all catalysts.

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ACKNOWLEDGMENT

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Conclusion High yields and excellent enantioselectivities were obtained for most of the substrates studied using various Ir-N,Pcomplexes. The ∆pKa values that have been calculated for the Ir-complexes using DFT indicate that there is a trend in the decrease of the acidity of the metal hydrides with increasing basicity of the heterocyclic ligand. The selectivity model was successfully used to confirm the observed and predicted absolute configuration of the products of hydrogenation.

ASSOCIATED CONTENT Supporting Information Experimental procedures, spectroscopic and computational data. This material is available free of charge via the Internet at http://pubs.acs.org

AUTHOR INFORMATION Corresponding Author

The Swedish Research Council (VR), Stiftelsen Olle Engkvist Byggmastare and The Swedish Energy Agency supported this work. All computations were carried out using the computational cluster resources at the National Supercomputer Center based at Linköping University, Sweden. Jia-Qi Li thanks the National Natural Science Foundation of China (No. 21402234) and Chinese Universities Scientific Fund (2014XJ034). Jianguo Liu thanks the Guangzhou Elite Scholarship Council for the PhD fellowship. Napasawan Chumnanvej thanks VR/SIDA for the three-month exchange fellowship to Stockholm University. Thishana Singh acknowledges the NRF South Africa and the College of Agriculture, Engineering and Science, University of Kwazulu-Natal, South Africa for the Postdoctoral Research Fellowship.

ABBREVIATIONS COD 1,5-cyclooctadiene; DFT Density Functional Theory; GC/MS Gas Chromatography Mass Spectroscopy; HPLC High Performance Liquid Chromatograpy.

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ACS Catalysis

Authors are required to submit a graphic entry for the Table of Contents (TOC) that, in conjunction with the manuscript title, should give the reader a representative idea of one of the following: A key structure, reaction, equation, concept, or theorem, etc., that is discussed in the manuscript. Consult the journal’s Instructions for Authors for TOC graphic specifications.

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Figure 1. Catalysts used in this study. 130x127mm (300 x 300 DPI)


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ACS Catalysis

Table 1. Asymmetric hydrogenation of γ-substituted cinnamyl alcohols 173x381mm (300 x 300 DPI)


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Table 2. Asymmetric hydrogenation of dialkyl substitut-ed allylic alcohols 190x432mm (300 x 300 DPI)


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ACS Catalysis

Table 3. Correlation of observed and predicted absolute configurations. 188x173mm (300 x 300 DPI)


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Figure 2. Quadrant model for predicting the absolute configuration in the asymmetric hydrogenation of trisubstituted alkenes using Ir-N,P-complexes. a) steric environment around Ir. b) 3-D model for asymmetric hydrogenation of allylic alcohols 10 and 12. 186x117mm (300 x 300 DPI)


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ACS Catalysis

Figure 3. a) Acid-base relationship of metal hydrides. b) pKaH of the protonated heterocycles and trend depicting the decrease of ∆pKa values in dichloromethane as the N donors varied. 261x163mm (300 x 300 DPI)


ACS Catalysis

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Figure 4. Performance of Ir-complexes in hydrogenation of acid sensitive compounds. 214x141mm (300 x 300 DPI)


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ACS Catalysis

Scheme 1. Intramolecular Friedel–Crafts alkylation catalyzed by Ir-complexes under H2 129x76mm (300 x 300 DPI)


ACS Catalysis

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Graphical Abstract 83x40mm (300 x 300 DPI)


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Asymmetric Hydrogenation of Allylic Alcohols Using IrâN,P

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